Narcolepsy type 1 is associated with loss of
orexin neurons, sleep-wake derangements,
cataplexy, and a wide spectrum of alterations in other physiological functions, including energy balance, cardiovascular, and respiratory control. It is unclear which
narcolepsy signs are directly related to the lack of
orexin neurons or are instead modulated by dysfunction of other
neurotransmitter systems physiologically controlled by
orexin neurons, such as the
histamine system. To address this question, we tested whether some of
narcolepsy signs would be detected in mice lacking
histamine signaling (HDC-KO). Moreover, we studied double-mutant mice lacking both
histamine signaling and
orexin neurons (DM) to evaluate whether the absence of
histamine signaling would modulate
narcolepsy symptoms produced by
orexin deficiency. Mice were instrumented with
electrodes for recording the electroencephalogram and electromyogram and a telemetric arterial pressure transducer. Sleep attacks fragmenting wakefulness,
cataplexy, excess rapid-eye-movement sleep (R) during the activity period, and enhanced increase of arterial pressure during R, which are hallmarks of
narcolepsy in mice, did not occur in HDC-KO, whereas they were observed in DM mice. Thus, these
narcolepsy signs are neither caused nor abrogated by the absence of
histamine. Conversely, the lack of
histamine produced
obesity in HDC-KO and to a greater extent also in DM. Moreover, the regularity of breath duration during R was significantly increased in either HDC-KO or DM relative to that in congenic wild-type mice. Defects of
histamine transmission may thus modulate the metabolic and respiratory phenotype of murine
narcolepsy.